Oxazolidinone cross-alkylation during Evans' asymmetric alkylation reaction

Article abstract of DOI:10.1016/j.tet.2011.09.083

Starting from Evans' imidazolidin-2-one (1) two compounds were obtained by trans-N-acylation: the expected one 3 with S,R configuration and a second compound 5, that is, related to 3 by the loss of a CH(CH₃)CO fragment. The stereochemistry of 3

Full text of DOI:10.1016/j.tet.2011.09.083

Tetrahedron 67 (2011) 9104e9111
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Oxazolidinone cross-alkylation during Evans’ asymmetric alkylation reaction
a
a
,
a
a
a
a
a
*
ꢀ
ꢀ
ꢀ
ꢀ
Nieves Fresno , Ruth Perez-Fernandez , Pilar Goya , M Luisa Jimeno , Ibon Alkorta , Jose Elguero ,
b,
b
*
ꢀ
Laura Menendez-Taboada , Santiago García-Granda
a
ꢀ
Instituto de Química Medica, IQM-CSIC, Juan de la Cierva, 3, E-28006 Madrid, Spain
b
ꢀ
Departamento de Química Física y Analítica, Facultad de Química, Universidad de Oviedo, Julian Clavería, 8, E-33006 Oviedo, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 July 2011
Received in revised form 16 September 2011
Accepted 20 September 2011
Available online 25 September 2011
Starting from Evans’ imidazolidin-2-one (1) two compounds were obtained by trans-N-acylation: the
expected one 3 with S,R configuration and a second compound 5, that is, related to 3 by the loss of
a CH(CH3)C]O fragment. The stereochemistry of 3 was established by NMR spectroscopy, mainly NOE
experiments, as expected, the new center has an S configuration, the compound being thus S,R. The
structure of compound 5 was determined by X-ray crystallography. A mechanism of formation of 5 was
proposed.
Keywords:
Oxazolidinone
Ó 2011 Elsevier Ltd. All rights reserved.
Asymmetric alkylation
X-ray crystallography
Multinuclear NMR
DFT calculations
1. Introduction
In early studies, it was shown that either lithium or sodium
hexamethyldisilazide bases (1.1 equiv of LiN[Si(CH3)3]2 or NaN
Compounds with an oxazolidine ring are of major interest be-
cause of their presence in several biologically active synthetic
products. Oxazolidin-2-ones are amongst the very few genuinely
new antimicrobial classes developed in the past 30 years, being
linezolid1,2 (Fig. 1) the only one marketed so far. Besides, their
usefulness as directing groups in asymmetric synthesis has been
fully tested. In the 1980s, Evans et al.3 and Masamune et al.4 re-
ported a series of chiral auxiliaries bearing an oxazolidine ring in
asymmetric reactions that proceeded with high stereoselectivity.
[Si(CH3)3]2), transformed imides to their respective Z-metal eno-
lates creating a diaestereofacial bias in the alkylation process with
more than 97% ee.5,6 This comes as a result of combining the ability
of acylated oxazolidinones to chelate to metal ions and the steric
hindrance caused by suitable substituents (R¼Bn, CHMe2) at the 4
position of the ring, in this case R has an R absolute configuration
(Scheme 1).
Scheme 1. Preparation of Z-metal enolates from (R)-(ꢀ)-4-substituted-3-propionyl-2-
oxazolidinones.
Fig. 1. Linezolid structure.
Nomura et al. have reported their observations of Evans’
asymmetric alkylation methodology in the synthesis of a selective
agonist for human peroxisome proliferator-activated receptor alpha
The asymmetric alkylation reactions arouse interest from
a synthetic, mechanistic, and theoretical point of view. The de-
velopment of N-acyl oxazolidinones as chiral enolate synthons in
carbonecarbon bond forming reactions has exhibited high levels of
diastereoselectivity in alkylation reactions.
(PPARa
).7 They stated that the sodium enolate derivative of their
oxazolidinones were less stable at temperatures above ꢀ78 ꢁC than
the corresponding lithium derivative, but with no mention to any
byproducts.
Some years earlier, parallel studies reported on the de-
velopment of a new class of chiral auxiliaries, the 5,5-substituted
SuperQuats, while focusing on up-scaling. The asymmetric
* Corresponding authors. Tel.: þ34 91562 2900; fax: þ34 91564 4853 (R.P.-F.); tel.:
þ34985102966;fax:þ34985103125(L.M.-T.);e-mail addresses: rperezf@iqm.csic.es
ꢀ
ꢀ
ꢀ
(R. Perez-Fernandez), menendezlaura.uo@uniovi.es (L. Menendez-Taboada).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.083

N. Fresno et al. / Tetrahedron 67 (2011) 9104e9111
9105
alkylations with SuperQuat auxiliaries using LiHMDS at ꢀ78 ꢁC
revealed the existence of byproducts with variable yields depend-
ing on the SuperQuat derivative used.8
2. Results and discussion
The purpose of this paper is to report our observations on the
effects of the organic base and temperature regarding Evans’
Scheme 4. The two diastereoisomers of compound 3.
asymmetric alkylation preparing chiral
a-methylphenylmetanoic
acid derivatives from acyl oxazolidinones (R¼Bn, CHMe2) and
methyl 3-bromomethyl benzoate. The effects of the organic base
(LiHMDS, NaHMDS, KOtBu) in a range of temperatures from ꢀ78 ꢁC
to room temperature on the reaction of oxazolidinones 1 and 2 with
benzyl 3-bromomethyl benzoate was explored.
At first, 1.1 equiv of NaHMDS (1.0 M in THF) were added to
a solution of oxazolidinone 1 in THF at ꢀ78 ꢁC. Thirty minutes after
the start of the reaction, methyl 3-bromomethyl benzoate was
slowly added. The reaction was completed in 6 h yielding the de-
sired (S)-configuration product, (S,R)-3, with 95% ee (Scheme 2).9
To establish independently the relative configuration of the
methyl group at 14-position, we have carried out B3LYP/6-
311þþG(d,p) calculations. One of the minimum energy conforma-
tions has an extended geometry (Fig. 2) being the (S,R) diaster-
oisomer 0.95 kJ molꢀ1 more stable than the (R,R) one, but this is
irrelevant since the stereochemistry of the new center is of kinetic
origin. To avoid cumbersome discussions we will assume that the
compound has the (S,R) configuration.
Fig. 2. Minimized structures of compound 3 [B3LYP/6-311þþG(d)]: left 14(S),4(R),
right 14(R),4(R).
We have used these geometries to calculate the chemical shifts
of both diastereoisomers (from the absolute shieldings calculated
at the GIAO approximation). They are very similar, preventing any
assignment (Table 1). We have reported the chemical shifts for the
13C NMR spectrum (at 75.47 MHz) and the chemical shifts and
1He1H coupling constants for the 1H NMR spectrum (at
499.98 MHz). For the aromatic protons only the chemical shifts are
reported (first order analyzed) but the two saturated fragments
(Me15eH14eH16aeH16b) and (H5aeH5beH4eH6aeH6b) were it-
eratively analyzed. It is not the aim of this paper to carry out
a conformational analysis of compound 3, thus we have used the
13C calculated chemical shifts of 3(S,R) together with 2D experi-
ments to assign the experimental signals (Table 1). From 13C we
have assigned unambiguously all the 1H attached to a given carbon
atom, including the equivalent ortho and meta carbons at 8, 9, 11,
and 12 positions.
Scheme 2. Synthesis of compounds 3 and 4. Reagents and conditions: (i) NaHMDS
1.0 M in THF, methyl 3-bromomethyl benzoate, THF dry, ꢀ78 ꢁC, 7 h.
When 1.1 equiv of LiHMDS (1.6 M in THF) were used instead of
NaHMDS at ꢀ78 ꢁC, compounds (S,R)-3 and (S,R)-4 were obtained
in very low yields. Subsequently, the reaction at ꢀ20 ꢁC was
attempted expecting the corresponding lithium enolate derivative
of the oxazolidinones to be more stable at higher temperatures
than the sodium enolate one, but surprisingly the final compounds
(S,R)-3 and (S,R)-4 were also obtained in very low yields.
From a practical point of view it was not convenient to perform
reactions at a very low temperature. We looked for a base that could
work at room temperature like the potassium tert-butoxide.
In a similar fashion the reactions were set up this time using
1 equiv of KOtBu and changing the reaction temperature to room
temperature.
Unexpectedly, the major product of the reaction was compound
5 obtained with a 62% yield (Scheme 3). The loss of the propionic
group was confirmed with NMR experiments and X-ray crystallo-
graphic analysis of the structure.
The only assignments that remain concern are the methylene
protons at 5, 6, and 16 positions.
Concerning the ring fragment C4C5, we have calculated the
spinespin coupling constants (SSCC) of the model compounds re-
ported in Fig. 2 at the B3LYP/6-311þþG(d,p) level optimizing pre-
vious B3LYP/6-31G(d) optimizations (frequencies were calculated
to verify that they were minima). Since the oxazolidin-2-one ring is
not planar, there could be a fast ring flipping12e14 and the experi-
mental SSCC should be compared to the average ones (Fig. 3).
The agreement is acceptable providing an assignment of H5a
[4.181 ppm, 3J¼8.03 (H4)] and H5b [4.117 ppm, 3J¼2.89 (H4)].
The 3JHH coupling constants and the Karplus equation15e17 were
used to check if the torsion angles of the optimized (S,R) structure
agreed with those deduced from the Karplus equation. The opti-
mized structure calculated (top of Table 1) was one example among
the different possibilities. For going from 3Jvic SSCC to torsion angles
Scheme 3. Synthesis of compound 5 from 1. Reagents and conditions: (i) t-BuOK,
Methyl 3-bromomethyl benzoate, THF dry, 7 h.
2.1. Determination of the stereochemistry of compound 3
ꢀ
The synthesis of 3 (Scheme 2) affords a unique compound with
the benzyl group of the oxazolidinone in a (R) configuration, cor-
responding to that of the starting 1, and an unknown configuration
of the methyl group of the lateral chain (Scheme 4). According to
the synthetic methodology used, the second center should be (S),
obtaining 3 (S,R).
we have used the software created by Navarro-Vazquez et al. that
takes into account the substituents linked to the different CeC
fragments, in our case CH3 (instead of CH2Ph), CONH2 (instead of
NeCOeR), Ph, and CH2OR (instead of CH2eO-ring).18 We have
calculated several conformations and adjusted the populations to
reproduce the SSCC.

9106
N. Fresno et al. / Tetrahedron 67 (2011) 9104e9111
Table 1
Experimental (1H at 499.88 MHz and 13C at 75.47 MHz) and calculated 1H and 13C chemical shifts of compound 3 S,R
Atom
1H
H4
Experimental chemical shifts
4.670
Experimental coupling constants
S,R calculated chemical shifts
R,R calculated chemical shifts
3J¼9.46 (H6a)
3J¼8.03 (H5a)
3J¼3.41 (H6b)
3J¼2.89 (H5b)
2J¼ꢀ9.17 (H5b)
3J¼8.03 (H4)
4J¼0.68 (H6a)a,b
2J¼ꢀ9.17 (H5a)
3J¼2.89 (H4)
2J¼ꢀ13.45 (H6a)
3J¼3.41 (H4)
4J¼0.68 (H5a)a
2J¼ꢀ13.45 (H6b)
3J¼9.46 (H4)
d
4.35
4.38
H5a
4.181
3.89
3.84
H5b
H6a
4.117
3.123
4.09
3.45
4.03
3.53
H6b
2.573
2.38
2.37
H8, H12 (ortho)
H9, H11 (meta)
H10 (para)
H14
7.05
7.26
7.26
4.107
7.36
7.33
7.30
3.75
7.38
7.34
7.24
3.99
d
d
3J¼7.02 (CH3)
3J¼7.16 (H16a)
3J¼7.33 (H16b)
3J¼7.02 (H14)
2J¼ꢀ13.46 (H16b)
3J¼7.16 (H14)
2J¼ꢀ13.46 (H16a)
3J¼7.33 (H14)
d
H15 (CH3)
H16a
1.193
2.729
0.92
2.10
0.93
3.18
H16b
3.207
3.40
2.18
H18
H20
H21
H22
7.93
7.90
7.37
7.51
3.87
8.76
7.94
7.17
7.22
3.76
8.74
7.96
7.10
7.18
3.73
d
d
d
H24 (CH3)
singlet
13C
C2 (C]O)
C4
C5
C6
C7
C8, C12 (ortho)
C9, C11 (meta)
C10 (para)
C13 (C]O)
C14
C15 (CH3)
C16
C17
C18
C19
C20
C21
C22
C23 (C]O)
C24 (CH3)
153.45
55.58
66.40
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
d
151.39
59.47
65.14
151.49
59.86
64.67
38.21
38.56
38.86
135.55
129.76
129.33
127.74
176.60
39.98
137.99
129.22
128.82
127.08
175.57
43.77
138.34
129.08
129.00
126.58
175.83
43.84
17.13
39.92
13.25
41.98
12.87
43.17
139.98
130.81
139.67
128.89
128.23
134.37
167.49
50.94
141.18
132.36
131.23
128.08
126.72
134.53
166.04
50.95
141.28
132.49
131.20
127.92
127.06
133.97
164.63
52.65
a
Note that protons H5a and H6b are coupled (4J¼0.68 Hz) due to their W or M pattern (HeCeCeCeH).10
b
4
The coupling on this signal is difficult to measure due to the benzylic JHH coupling constant of similar magnitude (for benzylic coupling constants see Ref. 11).

N. Fresno et al. / Tetrahedron 67 (2011) 9104e9111
9107
4JW¼0.68 Hz (with H5a) belongs to this fragment. The following
Karplus calculated coupling constants correspond to the three
conformations of Scheme 7, A (3.69 and 11.89 Hz), B (2.53 and
3.43 Hz), and C (11.98 and 2.79 Hz). A linear model led to the fol-
lowing values 71% of A (that corresponded to our minimized ge-
ometry), 29% of B, and 0% of C.
H4a
H4a
H4a
H3C
O
H3C
O
H3C
O
CH3
H4b
CH3
4
N
4
4
N
N
5
5
O
5
O
H5a
H5b
H5a
H5b
H5a
H5b
O
conformation B
conformation A
2
2
J
=
J
4a4b = – 6.72
gem
2Jgem
=
2J5a5b = – 7.39
2
3
2
2
3
2
J
=
J
5a5b = – 7.30
4a5a = + 7.37
J
J
=
J
5a5b = – 7.44
4a5a = + 7.77
gem
gem
3
3
3
3
J
J
J
J
=
=
trans
trans
J
4a5a = + 7.74
4b5b = + 8.09
J
=
J
=
J
cis
cis
cis
cis
3
3
3
3
J
3
3
3
3
3
3
J
C
=
=
J
4a5b = + 0.68
J
=
J
4a5b = + 8.86
J
=
4a5b = + 0.84
C
C
trans
trans
J
4b5a = + 10.03
H6b
H4
Ph
H4
H6a
H4
H6b
N
Ph
N
H6a
N
3Jcis(av) = + 7.92
Average (25% A, 75% B): Jgem = –7.40, 3Jcis = + 7.67,
2
3Jtrans (av) = + 5.36
3Jtrans = + 2.84
Exp. (compound 3): Jgem = – 9.17; 3Jcis = + 8.03; 3Jtrans = + 2.89
2
H6a
H6b
Ph
A
Fig. 3. Calculated and experimental coupling constants for the C4C5 fragment.
B
C
Scheme 7. The three staggered conformations of compound 3 about the C4-C6 bond.
(i) Fragment C14eC16 (CHMeeCH2). We have measured two
3Jvic (Table 1) of H14 with H16a (7.16 Hz) and H16b (7.33 Hz), the
corresponding dihedral angles ɸ being 178.9ꢁ and 62.3ꢁ according
to the optimized structure (Fig. 2, 3 S,R). Assuming two other
staggered structures obtained from this one and rotating about the
C14eC16 bond by 120 and 240ꢁ, three conformations were ob-
tained (Scheme 5).
In conclusion, the calculated minimum energy conformation is
only one of the minima in a complex surface.
Taking into account the conformations deduced from the Kar-
plus equation, it appears that the relative configuration of the C14
atom (15-methyl group position and H14), could be established by
selective NOE experiments with the CH2 at 6 position. Table 2
summarized the results of the NOE selective experiments. From
these experiments it is clear that the stereochemistry of C14 is (S)
confirming the stereochemistry of 3 as (S,R).
Me
Me
Me
H16b
H16a
H14
Ar
H16a
CO
Ar
H16b
CO
Table 2
Selective NOE experiments
H14
CO
H14
Irradiated signal
Chemical shift Affected signal
Unaffected signal
H16b
H16a
Ar
Methyl group, H15 1.193
4.107 (H14)
3.123 (H6a)
2.573 (H6b)
3.207 (H16b)
2.729 (H16a)
7.51 (H22)
A
B
C
Scheme 5. The three staggered conformations of compound 3 about the C14eC16
bond.
7.93 (H18)
H6a
H4
3.123
4.670
4.670 (H4)
4.107 (H14)
2.573 (H6b)
7.05 (Hortho, H8, H12)
7.93 (H18)
2.573 (H6b)
3.123 (H6a)
4.181 (H5a)
7.05 (Hortho, H8, H12)
1.193 (Me15)
1.193 (Me15)
The calculated Karplus values of 12.85 and 3.58 Hz corresponded to
an optimized conformation A, conformation B corresponded 2.80
and 3.17 Hz, and to conformation C corresponded the calculated
Karplus values of 3.97 and 12.86 Hz. A linear model led to the fol-
lowing values, 40% of A, 20% of B, and 40% of C.
(ii) Fragment C4C5 (CHRCH2) of the oxazolidin-2-one. Two very
different vicinal coupling constants, 8.03 (H4H5a) and 2.89 Hz
(H4H5b) related to 22.8 and 102.5ꢁ in the optimized geometry were
measured. But, as it was shown in Fig. 3, there could be another
conformation corresponding to the ring inversion (Scheme 6). This
conformation was optimized independently and it resulted to be
less stable.
2.2. Determination of the structure of compound 5
Compound 5 gave crystals suitable for X-ray analysis. The mo-
lecular structure of compound 5 is represented projected along the
a-axis in Fig. 4 (left) while the unit-cell view down a-axis is shown
in Fig. 4 (right).
A
B
Scheme 6. The two flipped conformations of compound 3 about the C4eC5 bond.
There is no doubt that the proton with the larger coupling cor-
responds to H5a at 4.181 ppm. Using the Karplus equation the four
calculated values of Scheme 6 were 82% of A (that of our optimized
structure) and 18% of B.
The fact that H5a (4.181 ppm) is coupled with H6a with
a
4JW¼0.68 Hz has being essential for the assignment of H6a and
H6b (see iii).
(iii) Fragment C4eC6 (CHringeCH2). The two coupling constants
of 9.46 Hz (2.573 ppm) and 3.41 (3.123 ppm) together with the
Fig. 4. View of compound 5 along the a-axis (left) and its unit cell (right).

9108
N. Fresno et al. / Tetrahedron 67 (2011) 9104e9111
Table 3
Crystal packing views are shown in Figs. 5 and 6. The single
Crystal data and structure refinement for compound 5
crystal X-ray structure data are listed in Table 3. Hydrogen-bonding
geometry is presented in Table 4.
Compound 5
Empirical formula
Formula weight
Temperature (K)
C19 H19 N O4
325.35
100
ꢁ
Wavelength (A)
1.54184
Monoclinic
P21
7.0958(1)
32.9935(6)
28.2202(5)
90.377(2)
32.9935(6)
16
Crystal system
Space group
ꢁ
a (A)
ꢁ
b (A)
ꢁ
c (A)
b
(ꢁ)
ꢁ
b (A)
Z
m
(mmꢀ1
)
0.753
F(000)
2752
Crystal size (mm)
Reflections collected
Unique reflections
R(int)
0.51ꢂ0.25ꢂ0.07
47,287
23,654
0.0340
R1[I>2
s
(I)]
0.0401
wR2 (all data)
0.1015
Absolute structure parameter
0.09(9)
Table 4
Hydrogen-bond geometry (A,
ꢁ
ꢁ
)
DeH/A
DeH
H/A
D/A
DeH/A
C31eH31/O2a
C126eH126/O14
C12eH12/O6
0.98
0.98
0.98
0.98
0.98
0.93
0.93
0.93
0.93
0.93
0.93
0.97
2.25
2.27
2.31
2.32
2.57
2.64
2.71
2.86
2.59
2.57
2.58
2.95
3.227 (3)
3.253 (3)
3.291 (3)
3.293 (3)
3.511 (3)
3.563 (3)
3.637 (3)
3.778 (3)
3.505 (3)
3.472 (3)
3.469 (3)
3.799 (3)
176
176
174
174
160
171
175
171
167
163
161
147
C69eH69/O26a
C107eH107/O18
C15eH15/Cg6b
C114eH114/Cg9b
C53eH53/Cg21c
C34eH34/Cg18c
C72eH72/Cg24d
C133eH133/Cg12e
C142eH30B/Cg24f
Fig. 5. Crystal packing. View along c.
Symmetry codes.
a
xꢀ1, y, z.
b
ꢀxþ1, yꢀ1/2, ꢀzþ1.
c
ꢀxþ1, yþ1/2, ꢀzþ1.
d
ꢀx, yþ1/2, ꢀzþ1.
e
ꢀxþ1, yꢀ1/2, ꢀz.
f
xþ1, y, z.
Fig. 6. Crystal packing. View along a.
As shown in Fig. 7 the crystal packing of compound 5 shows
chains along a crystallographic axis formed by hydrogen bonds
(eCeH/O]Ce). Chains are stabilized by very weak
pep in-
teractions between aromatic rings within the chain, but according
to centroidecentroid distances between two aromatic rings and the
angles between the normal of the benzene ring and the centroid
vector, only
four pairs of centroids. eHe
p
e
p
stacking interaction can be justified in one of the
interactions between these chains
Fig. 7. Hydrogen bonds in compound 5 (C(12)eH(12)/O(6) y C(31)eH(31)/O(2)).
Chains along a. View along c.
p

N. Fresno et al. / Tetrahedron 67 (2011) 9104e9111
9109
also contribute to the crystal packing forming layers along b crys-
tallographic axis (Figs. 8 and 9).
enolate gives rise to the ketene and the concomitant oxazolidinone
anion attacks the benzyl bromide derivative (Scheme 8).
Fig. 8. Hep interaction (C15eH15/Cg6).
Scheme 8. Proposed mechanism for the 1 to 5 transformation.
3. Conclusions
The reaction of (R)-(ꢀ)-4-benzyl-3-propionyl-2-oxazolidinone
with methyl 3-bromomethyl benzoate in basic medium afforded
two different compounds, 3 and 5, depending on the experimental
conditions. Both products were identified by NMR, MS and, one of
them (5), by X-ray crystallography. Compound 3 is a useful in-
termediate in the design of PPAR (Peroxisome Proliferator-
Activated Receptor) ligands,7,21 whereas compound 5 has been
found as substructure in cholesteryl ester transfer protein (CETP)
inhibitors, such as Anacetrapib.22,23 Both structures could be de-
veloped into bioactive ligands to treat metabolic disorders.
Fig. 9. Hep interaction (C15eH15/Cg6 and C34eH34/Cg18), forming layers along b.
The crystal packing of compound 5 shows chains along a crys-
tallographic axis, formed by hydrogen bonds (eCeH/O]Ce), as
shown in Fig. 7. Chains are stabilized by very weak pep interactions
between aromatic rings within the chain, but according to cen-
troidecentroid distances between two aromatic rings and the an-
gles between the normal of the benzene ring and the centroid
4. Experimental section
4.1. General
All chemicals were purchased from commercial suppliers and
used without further purification. TLC: precoated silica-gel 60 254
plates (Merck), detection by UV light (254 nm). Flash-column
Chromatography (FC): Kieselgel 60 (230e400 mesh; Merck).
Melting points (mp) were determined in open capillaries with
a Gallenkamp capillary melting-points apparatus and are un-
corrected. 1H and 13C NMR spectra were recorded on Bruker Ad-
vance 300 spectrometer operating at 300.13 MHz and 75.47 MHz,
respectively, in CDCl3 as solvent. In the case of the 1H NMR spec-
trum of 3 in CDCl3 we record the spectrum a Varian Inova 400 NMR
spectrometer, equipped with a 5-mm broadband probe, operating
at 399.90 MHz. Chemical shifts are reported in parts per million on
vector, only
four pairs of centroids. eHe
also contribute to the crystal packing forming layers along b crys-
tallographic axis (Figs. 8 and 9) (Table 5).
p
e
p
stacking interaction can be justified in one of the
interactions between these chains
p
Table 5
interactions (A, ꢁ, J). Where Alpha¼dihedral angle between planes I and J,
ꢁ
pe
p
Beta¼Angle Cg(I)/Cg(J) or Cg(I)/Me vector and normal to plane I, Gamma¼angle
Cg(I)/Cg(J) vector and normal to plane J (ꢁ) and CgeCg¼distance between ring
centroids
Cg(I) Cg(J)
d CgeCg
Alpha
Beta
Gamma Symmetry code
x, y, z
Cg(5) ꢃ Cg(2) 3.8720(14) 13.2493 13.09(11) 24.11
the
d scale. In the case of multiplets, the signals are reported as
intervals. Signals were abbreviated as s, singlet; d, doublet; t,
triplet, and m, multiplet. Coupling constants are expressed in hertz.
ROESY spectrum was obtained using the Varian standard pulse
sequence with a mixing time of 200 ms. For this spectrum, 32
transients were collected for each of 200 increments in F1. The data
were processed with Gaussian apodizations in each dimension and
backward linear prediction was applied in F1 followed by DC cor-
rections. NOESY1D spectra were collected employing a homospoil
gradient pulse for randomization of magnetization prior to the
relaxation delay. Sech180 shaped pulses were used for selective
excitation of specific resonances. LC-MS analyses were performed
The NMR spectrum of five in CDCl3 solution is reported in the
experimental part being fully consistent with the proposed
structure.
Since compound 5 crystallizes with Z0¼6 we decided to record
its 13C and 15N CPMAS NMR spectra by analogy with camphopyr-
azole,19,20 a compound with Z0¼6 where all the signals were split up
to six peaks. Unfortunately, no splitting was observed in any case.
The reaction mechanism of this cross-alkylation is thought to be
as follows: first the potassium tert-butoxide deprotonates the
alpha-hydrogen. Upon addition of the bromide derivative the

9110
N. Fresno et al. / Tetrahedron 67 (2011) 9104e9111
using an Alliance 2695 (Waters) with a diode array UVevis de-
tector Waters 2996 and interfaced to a Micromass ZQ mass spec-
trometer. Analyses were performed using reversed phase HPLC
NMR simulations. All measurable chemical shifts and couplings
constants for compound 3 were obtained from the experimental 1H
spectrum. Chemical shifts and coupling constants, measured for the
silica based columns: SunfireÔ C 18 3.5
m
m (4.6ꢂ50 mm). Using an
two
saturated
fragments
(Me15eH14eH16aeH16b)
and
injection volume of 10 L, a flow rate of 1 mL/min and gradient
m
(H5aeH5beH4eH6aeH6b), were then submitted (negative values
elution (5e95% over 18 min) or (10e100% over 5 min) of acetoni-
trile in water. Acetonitrile contains 0.08% v/v and water contains
0.1% v/v formic acid. Analyses were monitored at 254 nm
wavelength.
for the geminal couplings and positive values for the vicinal cou-
plings) to
a spectral simulation and optimization program
(gNMR5.0, IvorySoft, UK)24 that obtained a complete set of opti-
mized values by comparing experimental with simulated spectra.
For the two former fragments, dihedral angles were obtained
from the optimized coupling constants values by using the
Haasnoot-de Leeuw-Altona equation for three substituents (HLA),
as implemented in the Mestre-J program. However, the in-
terpretation of vicinal coupling constants in terms of a unique di-
hedral angle can be complicated by conformational mobility since
coupling constants may be time averages over multiple confor-
mations. In those cases we used a rotameric model and the vicinal
coupling constants were estimated for all the conformers from the
corresponding dihedral angles of the calculated conformers. Finally,
populations of the conformers were calculated solving systems of
linear equations using the Choleski method.25
4.2. Synthesis of methyl 3-[(S)-3-((R)-4-benzyl-2-
oxooxazolidin-3-yl)-2-methyl-3-oxopropyl]benzoate (3)
A
solution of (R)-(ꢀ)-4-benzyl-3-propionyl-2-oxazolidinone
(500 mg, 2.15 mmol) in anhydrous THF (11 mL) was stirred for
15 min under nitrogen atmosphere at ꢀ78 ꢁC. Then sodium bis(-
trimethylsilyl)amide 1.0 M in THF (2.36 mL, 2.36 mmol) was added
dropwise with a syringe to the stirred solution. The reaction mixture
was allowed to stir for 1 h at ꢀ78 ꢁC. Methyl 3-bromomethyl ben-
zoate (541 mg, 2.3 mmol) was added and the reaction stirred at this
temperature for 6 h. After reaching room temperature a saturated
solution of NH4Cl (15 mL) was added and the reaction extracted with
ethyl acetate (30 mL). The combined organic extracts were washed
successively with water (30 mL), brine (30 mL), and dried over
Na2SO4. The solvent was evaporated and the crude purified by silica
column chromatography (hexane/ethyl acetate 6:4 v/v) yielding
awhite solid (432 mg, 62%). Mp 98 ꢁC. LC-MS rt¼5.4, m/z: 382 (100%)
[MþH]þ. Elemental analysis calcd for C22H23NO5% C, 69. 28; H, 6.08;
N, 3.67; found C, 69.36; H, 5.87; N, 3.94.
Reduced/Convent
Input/Reduced
T¼Input/Convent: a0¼Tꢂa
Det (T) 1.000
!
!
ꢀ1
0
0
0
0
ꢀ1
0
ꢀ1
0
ꢂ
ꢀ1
0
0
0
0
ꢀ1
0
ꢀ1
0
¼
Cell lattice
a
b
c
Alpha
Beta
Gamma
Volume
Crystal
system
Laue
Input mP
Reduced mP
Convent mP
7.096
7.096
7.096
32.993
28.220
32.993
28.220
32.993
28.220
90.00
90.00
90.00
90.38
90.00
90.38
90.00
90.38
90.00
6607
6607
6607
Monoclinic
2/m
2/m
Monoclinic
Space group¼P21
-No obvious space group change needed/suggested.
4.3. Synthesis of (R)-methyl.3-[(4-benzyl-2-oxooxazolidin-3-
yl)methyl]benzoate (5)
Computational details. The geometry of the molecules has
been fully optimized with the hybrid HF/DFT B3LYP32 computational
method and the 6-31G(d) basis set.33 Frequency calculations have
been carried out at the same computational level to verify that the
structures obtained correspond to energetic minima. A further opti-
mization has been carried out at the B3LYP/6-311þþG(d,p) level.34
These geometries have been used for the calculations of the abso-
lute chemical shieldings with the GIAO method35 and the B3LYP/6-
311þþG(d,p) computational level. All the calculations have been
carried out with the Gaussian-09 package.36 The following equations
have been used to transform absolute shieldings into chemical shifts:
To a solution of (R)-(ꢀ)-4-benzyl-3-propionyl-2-oxazolidinone
(1200 mg, 5.24 mmol) in anhydrous THF (13 mL) was added
potassium tert-butoxide (600 mg, 5.24 mmol) and stirred for
45 min under nitrogen atmosphere at room temperature. Then
methyl 3-bromomethyl benzoate (1000 mg, 4.36 mmol) was
added to the stirred solution. The reaction mixture was stirred
for 6 h. A saturated solution of NH4Cl (15 mL) was added and
the reaction extracted with ethyl acetate (30 mL). The combined
organic extracts were washed successively with water (30 mL),
brine (30 mL) and dried over Na2SO4. The solvent was evapo-
rated and the crude purified by silica column chromatography
(hexane/ethyl acetate 7:3 v/v) yielding a white solid (432 mg,
62%). Mp 62 ꢁC. LC-MS rt¼4.8, m/z: 326 (100%) [MþH]þ. Anal.
Calcd for C19H19NO4% C, 70.14; H, 5.89; N, 4.31; found C, 70.31;
d
1H ¼ 31:0 ꢀ 0:97 ꢂ
s
1H
(1)
(reference TMS, 0.00 ppm).37
d
13C ¼ 175:7 ꢀ 0:963 ꢂ
s
13C
(2)
H, 5.67; N, 4.60. 1H NMR (300 MHz, CDCl3)
d 8.06e7.95 (m,
(reference TMS, 0.00 ppm).38
1HAr), 7.90 (s, 1HAr), 7.54e7.40 (m, 2HAr), 7.36e7.22 (m, 3HAr),
7.12e7.02 (m, 2HAr), 4.86 (d, 1H), 4.18 (m, 2H), 4.10e4.02 (m,
1H), 3.93 (s, 3H), 3.89e3.77 (m, 1H), 3.09 (dd, Jab¼13.6,
Ja4¼4.7 Hz, 1HCH2eAr), 2.66 (dd, Jba¼13.6, Jb4¼8.9 Hz, 1HCH2-Ar).
d
15N ¼ ꢀ152:0 ꢀ 0:946 ꢂ
s
15N
(3)
(reference ext. neat MeNO2, 0.00 ppm).38
13C NMR (75 MHz, CDCl3)
d 166.5 (C20), 157.9 (C2), 136.4 (C7),
Crystal structure determination. Suitable crystals for X-ray dif-
fraction experiments were obtained by crystallization of 5 in
a mixture of hexane/ethyl acetate.
135.4 (C14), 132.4 (C19), 130.8 (C16), 129.3 (C9), 129.1 (C11),
129.0 (C18), 128.9 (C8), 127.1 (C10), 67.0 (C5), 55.5 (C4), 51.9
(C21), 45.9 (C13), 38.3 (C6).

N. Fresno et al. / Tetrahedron 67 (2011) 9104e9111
9111
11. (a) See Ref. 10a (see p 776). (b) Froimowitz, M.; DiMeglio, C. M.; Makriyannis, A.
J. Med. Chem. 1992, 35, 3085; (c) Novak, A.; Bezensek, J.; Groselj, U.; Golobic, A.;
Stanovnik, B.; Svete, J. ARKIVOC 2011, vi, 18.
A crystal from compound 5 was used for data collection at 100 K
ꢁ
using CuK/
a
,
l
¼1.54184 A. A total of 47,287 (ꢀ8ꢄhꢄ8, ꢀ39ꢄkꢄ39,
ꢀ33ꢄlꢄ33) reflections were collected with 23,654 independent
reflections. Data collection was made using the program CrysAlis
CCD.26 An analytical numeric absorption correction27 was applied
to the intensity data.
12. Bongini, A.; Cardillo, G.; Orena, M.; Porzi, G.; Sandri, S. Tetrahedron 1987, 43,
4377.
ꢀ
ꢀ
13. Ciclosi, M.; Fava, C.; Galeazzi, R.; Orena, M.; Gonzalez-Rosende, M. E.; Sepul-
veda-Arques, J. Tetrahedron: Asymmetry 2004, 15, 1937.
14. Tomasini, C.; Angelici, G.; Castellucci, N. Eur. J. Org. Chem 2011, 20e21, 3648.
15. (a) Karplus, M. J. Chem. Phys. 1959, 30, 11; (b) Karplus, M. J. Phys. Chem. 1960, 64,
1793; (c) Karplus, M. J. Am. Chem. Soc. 1963, 85, 2870; (d) Emsley, J. W.; Feeney,
J.; Sutcliffe, L. H. High Resolution Nuclear Magnetic Resonance Spectroscopy;
Pergamon: Oxford, 1965; Vol. 2; 678.
Crystal structure was solved by Direct Methods, using the pro-
gram Sir2002.28 Anisotropic least-squares refinement was carried
out with SHELXL-97.29 Refinement was made in the space group
P21. Further details of the X-ray structural analysis are given in Table
3. Hydrogen bonds are listed in Table 4. Geometrical calculations
were made with PARST9730 and molecular graphics with ORTEP-
16. Haasnoot, C. A. G.; DeLeeuw, F. A. A. M.; Altona, C. Tetrahedron 1980, 36, 2783.
17. (a) Elguero, J.; Fruchier, A. An. Quim. 1974, 70, 141; (b) Jimeno, M. L.; Elguero, J.;
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Carmona, D.; Lamata, M. P.; San Jose, E. Magn. Reson. Chem. 1996, 34, 42; (c)
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31; (f) Del Bene, J.; Elguero, J. J. Phys. Chem. A 2006, 110, 12543.
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31 for Windows.
The Platon ADDSYM check results are the following:
Transformation matrix for cell and HKL data.
ꢀ
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Comput. Sci. 2004, 44, 1680.
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Crystallogr., Sect. C 1993, 49C, 724.
20. Yap, G. P. A.; Claramunt, R. M.; Lopez, C.; García, M. A.; Perez-Medina, C.; Al-
The following crystal structure has been deposited at the Cam-
bridge Crystallographic Data Centre and allocated the deposition
number: CCDC 835633. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK, (fax: þ44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
ꢀ
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korta, I.; Elguero, J. J. Mol. Struct. 2010, 965, 74.
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Thompson, C. F.; Anderson, M. S.; Chen, Y.; Eveland, S. S.; Guo, Q.; Hyland, S. A.;
Milot, D. P.; Sparrow, C. P.; Wright, S. D.; Cuminskey, A.-M.; Latham, M.; Pe-
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24. gNMR5.0, IvorySoft, AmorWay, Letchworth, Herts.SG61ZA, United Kingdom,
2004.
25. Press, W. H.; Teukolsky, S. A.; Vetterling, W. T.; Flannery, B. P. Numerical Recipes
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Acknowledgements
This work was supported by the Ministerio de Ciencia e
ꢀ
Innovacion (Project No. CTQ2009-13129-C02-02), Comunidad
ꢀ
Autonoma de Madrid (Project MADRISOLAR, ref. S-0505/PPQ/
0225), SAF2009-12422-C02-02, and RTA (RED Trastornos Adictivos
RD06/001/0014). The authors thank the CTI (CSIC) for allocation of
26. Oxford Diffraction. CrysAlis CCD, CrysAlis RED and CrysAlis PRO; Oxford Diffrac-
tion Ltd: Yarnton, England, 2009.
ꢀ
computer time and the Departamento de Química Organica y Bio-
ꢀ
organica (UNED) for recording the CPMAS NMR spectra. Financial
27. Clark, R. C.; Reid, J. S. Acta Crystallogr., Sect. A 1995, A51, 887.
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C.; Polidori, G.; Spagna, R. J. Appl. Crystallogr. 2003, 36, 1103.
29. Sheldrick, G. M. SHELXL-97 A computer program for refinement of crystal
ꢀ
support from Spanish Ministerio de Ciencia
e
Innovacion
ꢀ
(MAT2006-01997, MAT2010-15094 and ‘Factoría de Cristalizacion’
Consolider Ingenio 2010), and FEDER funding is acknowledged.
€
€
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